Systems and methods for treatment of allergies and other indications

ABSTRACT

The present invention generally relates to the transdermal delivery of various compounds. In some aspects, transdermal delivery may be facilitated by the use of a hostile biophysical environment. One set of embodiments provides a composition for topical delivery comprising an H 1  antihistamine and/or a salt thereof, and optionally, a hostile biophysical environment and/or a nitric oxide donor. In some cases, the composition may be stabilized using a combination of a stabilization polymer (such as xanthan gum, KELTROL® BT and/or KELTROL® RD), propylene glycol, and a polysorbate surfactant such as Polysorbate 20, which combination unexpectedly provides temperature stability to the composition, e.g., at elevated temperatures such as at least 40° C. (at least about 104° F.), as compared to compositions lacking one or more of these.

RELATED APPLICATIONS

This application is a national stage filing under 35 U.S.C. §371 ofInternational Patent Application PCT/US2011/067987, filed Dec. 29, 2011,which claims the benefit of U.S. Provisional Patent Application Ser. No.61/428,003, filed Dec. 29, 2010, entitled “Systems and Methods forTreatment of Allergies and Other Indications,” by E. T. Fossel; and ofU.S. Provisional Patent Application Ser. No. 61/428,213, filed Dec. 29,2010, entitled “Methods and Compositions for Preparing Emulsions forTopical Drug Delivery,” by E. T. Fossel. Each of these is incorporatedherein by reference in its entirety.

FIELD OF INVENTION

The present invention generally relates to transdermal delivery and, inparticular, to the transdermal delivery of H₁ antihistamines and othercompounds.

BACKGROUND

A histamine antagonist is an agent that inhibits action of histamine viahistamine receptors. H₁ antihistamines are used as treatment forsymptoms of allergies such as runny nose. Allergies are caused by anexcessive type 1 hypersensitivity response of the body to allergens,such as pollen released by plants. An allergic reaction, which if severeenough can lead to anaphylaxis, results in excessive release ofhistamines and other mediators by the body. Other uses of H₁antihistamines help with symptoms of local inflammation that resultsfrom various conditions, such as insect stings, even if there is noallergic reaction.

SUMMARY OF THE INVENTION

The present invention generally relates to the transdermal delivery ofH₁ antihistamines and other compounds. The subject matter of the presentinvention involves, in some cases, interrelated products, alternativesolutions to a particular problem, and/or a plurality of different usesof one or more systems and/or articles.

Several methods are disclosed herein of administering a subject with acomposition for prevention or treatment of a particular condition. It isto be understood that in each such aspect of the invention, theinvention specifically includes, also, the composition for use in thetreatment or prevention of that particular condition, as well as use ofthe composition for the manufacture of a medicament for the treatment orprevention of that particular condition.

In some embodiments, aspects of the invention relate to compositions fordelivering an H₁ antihistamine and/or a salt thereof to a subject. Insome embodiments, a composition comprises an H₁ antihistamine and/or asalt thereof in a hostile biophysical environment for topical deliveryto the skin of a subject. In some embodiments, a composition alsocomprises a nitric oxide donor. In some embodiments, a compositionfurther comprises one or more compounds that stabilize and/or otherwisepromote the efficacy of storage and/or delivery (e.g., with or without anitric oxide donor).

In some embodiments, compositions of the invention increase theefficiency of direct compound delivery to a target site by usingtransdermal delivery thereby significantly lowering the systemicexposure and reducing potential side effects. For example, a transdermaldelivery according to the invention can reduce systemic exposure to lessthan 10% (e.g., less than 5%, or between 0.1% and 1%, or even less) ofthe systemic exposure resulting from an oral dosage required foreffective delivery of the compound. For example, sedation effectsproduced by systemic diphenhydramine can be avoided by using a topicalformulation of the invention that provides sufficient local levels nearthe site of topical administration to be effective without producingsedation side-effects associated with the systemic levels that resultfrom oral administration. Also, in some embodiments, compositions of theinvention provide for unexpectedly high speeds of action of the compoundbeing delivered (e.g., relative to oral delivery or other deliverytechniques used for the compound). Accordingly, in some embodiments,aspects of the invention are useful for rapid therapy when delivery of atherapeutic amount of a compound within a short period of time isrequired. Topical delivery formulations described herein can deliver acompound to a target tissue more rapidly than an oral formulation, forexample. Topical delivery formulations also allow for targeted localdelivery of a therapeutically effective amount of compound withoutrequiring a significant systemic increase in the amount of compound.However, it should be appreciated that topical formulations can be usedfor systemic delivery if so required.

One aspect of the present invention is generally directed to acomposition, e.g., a composition for topical delivery to the skin of asubject. In one set of embodiments, the composition includes a nitricoxide donor, a hostile biophysical environment, a stabilization polymer,propylene glycol, a polysorbate surfactant, and an H₁ antihistamineand/or a salt thereof.

According to another set of embodiments, at least about 80% by weight ofthe composition comprises water, at least one chloride salt, a nitricoxide donor, a stabilization polymer, propylene glycol, a polysorbatesurfactant, and an H₁ antihistamine and/or a salt thereof.

In accordance with yet another set of embodiments, the compositionincludes a nitric oxide donor, a hostile biophysical environment, and anH₁ antihistamine and/or a salt thereof.

The composition, in still another set of embodiments, comprises orconsists essentially of water, sodium chloride, a nitric oxide donor,glyceryl stearate, magnesium sulfate and/or magnesium chloride,squalane, a stabilization polymer, isopropyl myristate, oleic acid,propylene glycol, a polysorbate surfactant, and an H₁ antihistamineand/or a salt thereof. The composition may also comprise or consistessentially of an antioxidant.

In yet another set of embodiments, the composition comprises or consistsessentially of water, sodium chloride, a nitric oxide donor, glycerylstearate, cetyl alcohol, magnesium sulfate and/or magnesium chloride,squalane, a stabilization polymer, isopropyl myristate, oleic acid,propylene glycol, a polysorbate surfactant, and an H₁ antihistamineand/or a salt thereof. The composition may also comprise or consistessentially of an antioxidant.

According to still another set of embodiments, the composition compriseseach of the following compounds at concentrations of no more than +20%of the stated concentrations: water at a concentration of about 35% toabout 55% by weight, sodium chloride at a concentration of about 2.5% toabout 15% by weight, a nitric oxide donor at a concentration of about2.5% to about 15% by weight, glyceryl stearate at a concentration ofabout 4% to about 10% by weight, cetyl alcohol at a concentration ofabout 4% to about 10% by weight, magnesium chloride at a concentrationof about 2.5% to about 15% by weight, squalane at a concentration ofabout 1% to about 8% by weight, a polysorbate surfactant at aconcentration of about 0.2% to about 2% by weight, isopropyl myristateat a concentration of about 0.1% to about 5% by weight, oleic acid at aconcentration of about 0.1% to about 5% by weight, propylene glycol at aconcentration of about 1% to about 10% by weight, a stabilizationpolymer at a concentration of about 1% to about 10% by weight, and an H₁antihistamine and/or a salt thereof at a concentration of about 0.1% toabout 5% by weight. The composition may also comprise an antioxidant ata concentration of about 0.1 to about 1% by weight.

The composition, in yet another set of embodiments, comprises each ofthe following compounds at concentrations of no more than +20% of thestated concentrations: water at a concentration of about 35% to about55% by weight, sodium chloride at a concentration of about 2.5% to about15% by weight, a nitric oxide donor at a concentration of about 2.5% toabout 15% by weight, glyceryl stearate at a concentration of about 4% toabout 10% by weight, magnesium chloride at a concentration of about 2.5%to about 15% by weight, squalane at a concentration of about 1% to about8% by weight, a polysorbate surfactant at a concentration of about 0.2%to about 2% by weight, isopropyl myristate at a concentration of about0.1% to about 5% by weight, oleic acid at a concentration of about 0.1%to about 5% by weight, propylene glycol at a concentration of about 1%to about 10% by weight, a stabilization polymer at a concentration ofabout 1% to about 10% by weight, and an H₁ antihistamine and/or a saltthereof at a concentration of about 0.1% to about 5% by weight. Thecomposition may also comprise an antioxidant at a concentration of about0.1 to about 1% by weight.

In some embodiments, a composition comprises approximately 7.5% (e.g.,1% to 15%, or more or less) by weight of antihistamine (e.g.,diphenhydramine or other antihistamine) in an oil/water emulsion furthercomprising about 10% sodium chloride, and about 5% magnesium chloride.For example, the antihistamine may be an H₁ antihistamine and/or a saltthereof.

In some embodiments, the pH of a composition is optimized to ionize theantihistamine while remaining compatible with acceptable pH ranges forcontact with the skin (e.g., within a range of about pH 5 to about pH8). In some embodiments, a pH at least about 1 pH unit above or below(e.g., at least about 2 pH units above or below) the pKa ofdiphenhydramine of 9.0 is sufficient to ionize the antihistamine. Insome embodiments, a pH of 7 (+/−1.0) is effective. In some embodiments,a pH of 7.2 (e.g., +/−0.5) is particularly effective fordiphenhydramine. In some embodiments, a pH at least about 1 pH unitabove or below the pKa of an antihistamine may be used, particularly ifthe pH is within the range of about pH 5.0-8.0 that is particularlycompatible for direct topical contact with skin. The antihistamine maybe, for instance, an H₁ antihistamine and/or a salt thereof, or anyantihistamine discussed herein.

According to aspects of the invention, a relatively high saltconcentration, for example at least about 2% (e.g., about 5%, about 10%about 15%, about 20% about 25%, about 25-50%, weight %) is useful toprovide a hostile biophysical environment that promotes transdermalmigration of an antihistamine (e.g., diphenhydramine). In someembodiments, emulsions described herein, for example, containing astabilization polymer and/or a polysorbate surfactant and/or propyleneglycol (or a low molecular weight glycol, or a polyglycol such aspolyethylene glycol or other polyglycol—however it should be appreciatedthat glycols with even numbers of carbons can be toxic, particularly forsmaller glycols such as ethylene glycol and butylene glycol, and shouldbe avoided or excluded) are unexpectedly effective at stabilizing theantihistamine in the high salt composition in a form that remainseffective for an extended period—for example, retaining rapidtransdermal delivery of the antihistamine for at least several weeks ormonths. In some cases, the antihistamine is an H₁ antihistamine (e.g.,diphenhydramine) and/or a salt thereof.

In still another set of embodiments, the composition includes astabilization polymer, propylene glycol, a polysorbate surfactant; andan H₁ antihistamine and/or a salt thereof.

In another set of embodiments, at least about 80% by weight of thecomposition comprises water, at least one chloride salt, a stabilizationpolymer, propylene glycol, a polysorbate surfactant, an antioxidant, andan H₁ antihistamine and/or a salt thereof.

The invention, in accordance with another aspect, is generally directedto a method. In one set of embodiments, the method is a method ofapplying any of the compositions described herein to a subject, e.g., tothe skin of a subject. The method, in accordance with another set ofembodiments, includes an act of applying, to a portion of the skin of asubject, a delivery vehicle comprising an H₁ antihistamine and/or a saltthereof in a hostile biophysical environment.

In still another set of embodiments, the method includes an act ofapplying, to at least a portion of the skin of a subject, a compositioncomprising a nitric oxide donor, a hostile biophysical environment, astabilization polymer, propylene glycol, a polysorbate surfactant, andan H₁ antihistamine and/or a salt thereof.

In another aspect, the present invention encompasses methods of makingone or more of the embodiments described herein, for example, acomposition comprising an H₁ antihistamine. In still another aspect, thepresent invention encompasses methods of using one or more of theembodiments described herein, for example, a composition comprising anH₁ antihistamine. In yet another aspect, the present inventionencompasses various uses of a composition including an H₁ antihistamine.For example, the composition may be used to treat an allergy.

In some embodiments, aspects of the invention relate to a patch thatcomprises a composition of the invention (e.g., with or without a nitricoxide donor, and with or without one or more stabilizing compounds). Insome embodiments, a composition is in the form of a cream or ointmentthat is incorporated into the patch. However, other configurations alsomay be used.

In some embodiments, aspects of the invention relate to methods andformulations for delivering a compound locally at a fraction of thesystemic dose required using oral delivery. In some embodiments, ahostile biophysical environment may be evaluated for enhancing localdelivery through a topical application. Depending on the therapeuticapplication, an appropriate delivery configuration (e.g., a combinationof compound concentration, hostile biophysical environment, cream,patch, etc.) can be used to reduce the systemic amount of the compoundrequired for an effective therapeutic application.

In some embodiments, aspects of the invention relate to topicalformulations and methods that can be used (e.g., when treating skinallergies) to reduce or avoid drowsiness often associated with oraladministration of a compound described herein. Topical formulationsdescribed herein also are faster acting than oral formulations.

Other advantages and novel features of the present invention will becomeapparent from the following detailed description of various non-limitingembodiments of the invention when considered in conjunction with theaccompanying figures. In cases where the present specification and adocument incorporated by reference include conflicting and/orinconsistent disclosure, the present specification shall control in theabsence of clear error. If two or more documents incorporated byreference include conflicting and/or inconsistent disclosure withrespect to each other, then the document having the later effective dateshall control.

DETAILED DESCRIPTION

The present invention generally relates to the transdermal delivery ofvarious compounds. In some aspects, transdermal delivery may befacilitated by the use of a hostile biophysical environment. One set ofembodiments provides a composition for topical delivery comprising an H₁antihistamine and/or an H₁ antihistamine salt, and optionally, a hostilebiophysical environment and/or a nitric oxide donor. In some cases, thecomposition may be stabilized using a combination of a stabilizationpolymer (such as xanthan gum, KELTROL® BT and/or KELTROL® RD), propyleneglycol, and a polysorbate surfactant such as Polysorbate 20, whichcombination unexpectedly provides temperature stability to thecomposition, e.g., at elevated temperatures such as at least 40° C. (atleast about 104° F.), as compared to compositions lacking one or more ofthese.

According to aspects of the invention, compositions comprising arelatively high salt composition (e.g., high chloride content) areunexpectedly effective for topical delivery of an H₁ antihistamine(including salts thereof), for example diphenhydramine. In someembodiments, a salt-enhanced delivery (e.g., in a composition having atleast 2% salt, at least 5% salt, at least 10% salt, at least 15% salt,or higher as described herein) is particularly effective when the pH ofthe composition is optimized to ionize the compound being delivered(e.g., at least about 80%, at least about 90%, at least about 95%, orabout 99% or more) is ionized. It should be appreciated that dependingon the pKa of the compound and the pH of the composition, the ionizedform may be anionic or cationic (e.g., due to protonation). In someembodiments, a compound may contain several ionizable groups each havinga different pKa. In some embodiments, it is sufficient for at least 1,2, or 3 of the groups to be ionized for the salt-enhanced delivery to beeffective. In some embodiments, an ionizable group is sufficientlyionized if the pH of the composition is at least 1 pH unit, or at least2 pH units (e.g., 1, 1-2, 2-3, or more pH units) below the pKa of thegroup and it is cationic (due to protonation) below its pKa. Similarly,in some embodiments, an ionizable group is sufficiently ionized if thepH of the composition is at least 1 pH unit, or at least 2 pH units(e.g., 1, 1-2, 2-3, or more pH units) above the pKa of the group and itis anionic (due to deprotonation) above its pKa. In some embodiments,the presence of magnesium chloride, for example at 0.1-5% by weight, canhelp stabilize composistions containing compounds with relatively highpKas (e.g., above 8.0, above 9.0, above 10.0 or higher). In someembodiments, the pH of a composition may be maintained using a buffer.However, the pH of compositions of the invention are surprisingly stablewithout a buffer. In some embodiments, a desired pH can be establishedby titrating the mixture with an acid (e.g., HCl) or a base (e.g.,NaOH). The pH of the resulting composition (e.g., when formulated as anemulsion as described herein) can be stable (e.g., sufficiently for thecomposition to be effective for transdermal delivery) for extendedperiods of time (e.g., weeks, months, or 1 or more years).

According to other aspects of the invention, a high salt compositioncontaining an H₁ antihistamine (including salts thereof) is unexpectedlystable when formulated as an emulsion (e.g., a water in oil emulsion oran oil in water emulsion, for example, including one or more of astabilization polymer and/or a polysorbate surfactant and/or propyleneglycol (or other low molecular weight glycol, or a polyglycol) asdescribed herein). In some embodiments, the pH of the compositioncomprising the emulsion and high salt concentration is selected toionize the compound being delivered as described herein.

In some embodiments, topical delivery according to the invention (e.g.,topical delivery of an H1 antihistamine (including salts thereof), forexample diphenhydramine) provides a surprisingly rapid effect (withinabout 1-5 minutes) on symptoms (e.g., hives or other allergic rashes orother symptoms). In contrast, current formulations of diphenhydraminetake significantly longer (e.g., about 40 minutes or more) to takeeffect. Accordingly, aspects of the invention provide methods andcompositions for delivering an effective treatment to a subject to treator prevent an allergy. In some embodiments, a topical composition isapplied to a region of inflamed skin (or skin that has a rash, or othersigns of allergy, including, for example, hives). In some embodiments, acomposition is provided to produce relief from symptoms of allergy inless than 1 hour, less than 30 minutes, less than 20 minutes, less than15 minutes, less than 10 minutes, or less than 5 minutes.

One aspect of the invention provides compositions for the topicaldelivery of substances such as pharmaceutical agents (e.g., drugs,biological compounds, etc.). The pharmaceutical agents may be applied tothe skin of a subject, e.g. a human, to aid in treatment of medicalconditions or diseases, and/or the symptoms associated thereof. In someembodiments, the invention provides for the treatment of medicalconditions or diseases and/or ailments using pharmaceutical agents (forexample, to treat a subject diagnosed with a medical condition ordisease, as described herein), and in some cases, the invention providesfor the delivery of a minimum amount of pharmaceutical agents to provideeffective levels of medication to an effected area topically whilelimiting side effects. In some cases, the effective dosage of thepharmaceutical agent may be lower than the effective dosage of thepharmaceutical agent when taken orally.

In one set of embodiments, the H₁ antihistamine may have a structure:

where X is CH, N, C(CH₃), or C(OH); the “Spacer” is usually 2-3 carbonsin length, and may be linear, ring, branched, saturated or unsaturated;and R¹ and R² each independently may be —H, or a substituted orunsubstituted alkyl group, e.g., —CH₃. In some cases, X may be a chiralcenter. In certain cases, the two aromatic rings can be orientated indifferent planes; for example, the tricyclic ring system may be slightlypuckered and the two aromatic rings may be arranged to lie in differentgeometrical planes.

Non-limiting examples of H₁ antihistamines include, but are not limitedto, fexofenadine (pKa of 13.20), cetirizine (pKa of 1.6-2.2, 2.9-3.0,8.0-8.3) (or levocertrizine), clemastine, diphenhydramine (pKa of8.2-9.1), doxylamine (pKa of 8.7-9.2), pheniramine (pKa of 4.2,9.3-9.4), ebastine, chlorpheniramine (pKa of 9.2-9.4), meclizine,embramine, dexchlorpheniramine, and loratadine (pKa of 4.9-5.0). Thestructures of these compounds are respectively shown below:

Accordingly, various aspects of the invention are directed tocompositions including an H₁ antihistamine for transdermal delivery ortopical application to a subject. Besides an H₁ antihistamine, othercompounds such as salts or derivatives of H₁ antihistamines are alsoincluded in other embodiments; thus, it should be understood that in anyembodiment described herein using an H₁ antihistamine, this is by way ofexample only, and other embodiments of the invention are directed to H₁antihistamine salts, H₁ antihistamine derivatives, etc., instead ofand/or in addition to H₁ antihistamines.

H₁ antihistamines or other pharmaceutical agents (e.g., salts orderivatives of H₁ antihistamines, etc.) may be present at any suitableconcentration. For instance, in some cases, the pharmaceutical agent maybe present at a concentration of at least about 0.1%, at least about0.3%, at least about 0.5%, at least about 0.7%, at least about 1%, atleast about 2%, at least about 3%, at least about 4%, at least about 5%,at least about 6%, at least about 7%, at least about 7.5%, at leastabout 8%, at least about 9%, or at least about 10% by weight of thecomposition. In certain embodiments, the pharmaceutical agent may bepresent at a concentration of no more than about 1%, no more than about2%, no more than about 3%, no more than about 4%, no more than about 5%,no more than about 6%, no more than about 7%, no more than about 8%, nomore than about 9%, no more than about 10%, no more than about 12%, nomore than about 15%, or no more than about 20% by weight of thecomposition. In addition, the pharmaceutical agent may be present innative form and/or as one or more salts. For example, if an H₁antihistamine is present, it may be used in its native form, and/or asone or more salts, e.g., the sodium salt, the potassium salt, themagnesium salt, the lysine salt, the arginine salt, the hydrochloridesalt, the tannate salt, the citrate salt, the acefylline salt, themaleate salt, etc. of an H₁ antihistimate, e.g., fexofenadine,cetirizine (or levocertrizine), clemastine, diphenhydramine, doxylamine,pheniramine, ebastine, chlorpheniramine, meclizine, embramine,dexchlorpheniramine, loratadine, etc. For salt forms of thepharmaceutical agent, “by weight of the composition” includes the entiresalt form of the pharmaceutical agent, e.g., the agent itself as well asany counterions such as sodium, potassium, etc. The amount of thepharmaceutical agent may be determined in a composition, for example,using techniques such as HPLC or HPLC/MS that are known to those ofordinary skill in the art.

Many H₁ antihistamines are readily commercially available. In somecases, the H₁ antihistamine may be obtained as a racemic mixture, forexample, for fexofenadine (e.g., (R)-fexofenadine and (S)-fexofenadine),or cetirizine (e.g., (R)-cetirizine and (S)-cetirizine). However, inother cases, one of the enantiomers may be present in an amount greaterthan the other. For example, at least about 60%, at least about 70%, atleast about 80%, at least about 90%, or at least about 95% of the H₁antihistamine within the composition may be present as one of theenantiomers. Techniques for preparing or separating racemic H₁antihistamines are known; see, for example, Fang, et al., “An Efficientand Facile Synthesis of Racemic and Optically Active Fexofenadine,”Tetrahedron Lett., 39:2701-2704, 1998; Liu, et al., “Direct Separationof the Enantiomers of Cetirizine and Related Compounds by Reversed-PhaseChiral HPLC,” Chromatographia, 56:233-235, 2002; Pflum, “A Large-ScaleSynthesis of Enantiomerically Pure Cetirizine Dihydrochloride UsingPreparative Chiral HPLC,” Org. Proc. Res. Dev., 5:110-115, 2001.

The composition may also comprise a nitric oxide donor in someembodiments, for example, L-arginine and/or L-arginine hydrochloride. Insome cases, such a nitric oxide donor may be used to increase localizedblood flow at the site where the composition is applied, which mayenhance delivery of the pharmaceutical agent. The nitric oxide donor maybe present at any suitable concentration within the composition. Forinstance, in some cases, the nitric oxide donor is present at aconcentration of at least about 1%, at least about 2%, at least about3%, at least about 4%, at least about 5%, at least about 6%, at leastabout 7%, at least about 7.5%, at least about 8%, at least about 9%, orat least about 10% by weight of the composition. In some cases, one ormore nitric oxide donors (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. nitricoxide donors) may be used. In some cases, there may be no more than 3,5, 7, or 10 nitric oxide donors present within the composition.

A “nitric oxide donor,” as used herein, is a compound that is able torelease nitric oxide and/or chemically transfer the nitric oxide moietyto another molecule, directly or indirectly, for example, through abiological process. The nitric oxide donor may release nitric oxide intothe skin, and/or tissues such as muscles and/or elements of thecirculatory system in close proximity to the surface of the skin.Non-limiting examples of nitric oxide donors include arginine (e.g.,L-arginine and/or D-arginine), arginine derivatives (e.g., L-argininehydrochloride and/or D-arginine hydrochloride), nitroglycerin,polysaccharide-bound nitric oxide-nucleophile adducts,N-nitroso-N-substituted hydroxylamines,1,3-(nitrooxymethyl)phenyl-2-hydroxybenzoate, etc., and/or anycombination of these and/or other compounds.

Besides L-arginine and L-arginine hydrochloride, other non-limitingexamples of nitric oxide donors include D,L-arginine, D-arginine, oralkyl (e.g., ethyl, methyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, etc.) esters of L-arginine and/or D-arginine (e.g., a methylester, an ethyl ester, a propyl ester, a butyl ester, etc.) and/or saltsthereof, as well as other derivatives of arginine and other nitric oxidedonors. For instance, non-limiting examples of pharmaceuticallyacceptable salts include hydrochloride, glutamate, butyrate, orglycolate (e.g., resulting in L-arginine glutamate, L-arginine butyrate,L-arginine glycolate, D-arginine hydrochloride, D-arginine glutamate,etc.). Still other examples of nitric oxide donors includeL-arginine-based compounds such as, but not limited to, L-homoarginine,N-hydroxy-L-arginine, nitrosylated L-arginine, nitrosylated L-arginine,nitrosylated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine,citrulline, ornithine, linsidomine, nipride, glutamine, etc., and saltsthereof (e.g., hydrochloride, glutamate, butyrate, glycolate, etc.),and/or any combination of these and/or other compounds. Still othernon-limiting examples of nitric oxide donors include S-nitrosothiols,nitrites, 2-hydroxy-2-nitrosohydrazines, or substrates of various formsof nitric oxide synthase. In some cases, the nitric oxide donor may be acompound that stimulates endogenous production of nitric oxide in vivo.Examples of such compounds include, but are not limited to, L-arginine,substrates of various forms of nitric oxide synthase, certain cytokines,adenosine, bradykinin, calreticulin, bisacodyl, phenolphthalein,OH-arginine, or endothelein, and/or any combination of these and/orother compounds.

Accordingly, it should be understood that, in any of the embodimentsdescribed herein that describe L-arginine and/or L-argininehydrochloride, other nitric oxide donors may also be used instead, or incombination with, L-arginine and/or L-arginine hydrochloride, in otherembodiments of the invention.

In some cases, the concentration of the nitric oxide donor within thecomposition may be tailored to have a duration of effective treatment ofat least about 3 hours, at least about 5 hours, or at least about 8hours or more in certain instances. The duration may also be controlled,for instance, by controlling the concentration of a penetrating agentused in conjunction with the nitric oxide donor. Penetration agents arediscussed in detail herein. The actual concentration for a particularapplication can be determined by those of ordinary skill in the artusing no more than routine experimentation, for example, by measuringthe amount of transport of the nitric oxide donor as a function ofconcentration in vitro across cadaver skin or suitable animal models,skin grafts, synthetic model membranes, human models, or the like.

As a particular non-limiting example, in certain embodiments, nitricoxide is provided using L-arginine, for example, at a concentration ofat least about 0.5% by weight (wt % or w/v) of L-arginine (optionallywith one or more penetrating agents as discussed herein, for example, apenetrating agent able to create a hostile biophysical environment), atleast about 0.75 wt %, at least about 1 wt %, at least about 2 wt %, atleast about 3 wt %, at least about 5 wt %, at least about 7 wt %, atleast about 10 wt %, or at least about 15 wt %. The L-arginine may bepresent in a suitable delivery vehicle, such as a cream or a lotion.L-arginine may be particularly useful in some cases due to its lowtoxicity, its high solubility, and/or its low cost. Other examples ofnitric oxide donors are discussed in International Patent ApplicationNo. PCT/US2005/005726, filed Feb. 23, 2005, entitled “Topical Deliveryof a Nitric Oxide Donor to Improve Body and Skin Appearance,” by E. T.Fossel, published as WO 2005/081964 on Sep. 9, 2005, incorporated hereinby reference.

Without wishing to be bound to any theory, it is generally believed thatthe flow of the pharmaceutical agent across the skin may slow as itbuilds up within the tissue. Fick's first law of diffusion suggests thatwhen the concentration inside becomes substantially equal to thatoutside, passive flow stops. The increased local blood flow may preventor at least decrease the stoppage of the flow of the pharmaceuticalagent. Thus, when the composition is applied to the skin, thepharmaceutical agent exits the vehicle into the tissue more readily, asthe pharmaceutical agent is dispersed by flow and does not build up inconcentration in the tissue. Thus, in certain embodiments,pharmaceutical agents may be introduced into the skin, for example, anH₁ antihistamine and/or a salt or derivative of an H₁ antihistamine,such as fexofenadine, cetirizine (or levocertrizine), clemastine,diphenhydramine, doxylamine, pheniramine, ebastine, chlorpheniramine,meclizine, embramine, dexchlorpheniramine, or loratadine. Accordingly,the composition may be delivered locally and/or systemically; initially,much of the delivery is at first local (i.e., through the skin), but insome cases, the pharmaceutical agents may also be distributedsystemically, e.g., upon reaching the blood supply.

The composition may also comprise a hostile biophysical environment toan H₁ antihistamine in some embodiments. In a hostile biophysicalenvironment, the environment surrounding the pharmaceutical agent (e.g.,an H₁ antihistamine, etc.) may be such that the pharmaceutical agent isin a chemically and/or energetically unfavorable environment, relativeto the skin (e.g., the chemical potential and/or the free energy of thepharmaceutical agent within the hostile biophysical environment issignificantly greater than the chemical potential and/or the free energyof the pharmaceutical agent within the skin, thus energetically favoringtransport into the skin), especially the stratum corneum.

Examples of such compositions are discussed in International PatentApplication No. PCT/US2005/013228, filed Apr. 19, 2005, entitled“Transdermal Delivery of Beneficial Substances Effected by a HostileBiophysical Environment,” by E. Fossel, published as WO 2005/102282 onNov. 3, 2005, incorporated herein by reference. Other techniques forhostile biophysical environments are discussed in detail herein.Accordingly, certain embodiments of the invention are generally directedto compositions for topical delivery to the skin of a subject comprisinga nitric oxide donor, a hostile biophysical environment, and apharmaceutical agent such as an H₁ antihistamine, or a salt or aderivative of an H₁ antihistamine, or the like.

A hostile biophysical environment of the invention can comprise, invarious embodiments, high ionic strength, a high concentration ofosmotic agents such as ureas, sugars, or carbohydrates, a high pHenvironment (e.g., greater than about 7, greater than about 8, greaterthan about 9, greater than about 10, greater than about 11, greater thanabout 12, or greater than about 13), a low pH environment (less thanabout 5, less than about 4, less than about 3 or less than about 2),highly hydrophobic components, or highly hydrophilic components or othersubstances that cause an increase in the chemical potential and/or freeenergy of the pharmaceutical agent, or any combination of two or more ofthese and/or other compounds. A hydrophobic component may, in someembodiments, have an octanol-water partition coefficient of at leastabout 100, at least about 1000, at least about 10⁴, at least about 10⁵,or more in some cases. Similarly, a hydrophilic component may have anoctanol-water partition coefficient of less than about 0.01, less thanabout 10⁻³, less than about 10⁻⁴, or less than about 10⁻⁵ in some cases.

In some cases, the composition defines the biophysical hostileenvironment. In other cases, a pharmaceutical agent may be packaged insuch a way that it is carried into tissue and/or its charge isneutralized by derivitization and/or by forming a neutral salt. Examplesof biophysically hostile environments include, but are not limited to,high ionic strength environments (e.g., by the addition of ureas,sugars, carbohydrates, and/or ionic salts such as lithium chloride,sodium chloride, potassium chloride, calcium chloride, magnesiumchloride, choline chloride, sodium fluoride, lithium bromide, etc.), aswell as combinations of these and/or other agents, for instance at highionic strengths (for example, greater than about 0.25 M, greater thanabout 1M, greater than about 2 M, greater than about 3 M, greater thanabout 5 M, greater than about 10 M, greater than about 15 M, greaterthan about 20 M, greater than about 25 M, etc., or in some cases,between about 0.25 M and about 15 M, between about 5 M and about 15 M,between about 10 M and about 15 M, etc.); high or low pH environments(e.g., by adding pharmaceutically acceptable acids or bases, forexample, such that the pH is between about 3 and about 7, between about3 and about 6, between about 3 and about 5, between about 4 and 8,between about 5 and about 8, between about 5 and 8.5, between about 7and about 11, between about 8 and about 11, between about 9 and about11, etc.); or highly hydrophobic environments (e.g., by decreasing watercontent and increasing lipid, oil and/or wax content of theenvironment). In some embodiments, the ionic strength is any amountgreater than two times the physiological ionic strength of blood. Theionic strength of a composition can be readily controlled in certainembodiments by controlling the amounts or concentrations of one or moreof the salts present in the composition, e.g., by controlling the amountof sodium chloride, magnesium chloride, choline chloride, etc., and/orother salts.

Other highly charged molecules such as polylysine, polyglutamine,polyaspartate, etc., or copolymers of such highly charged amino acidsmay also be used in certain embodiments to create the hostilebiophysical environment. Non-limiting examples of delivery vehicleswhich would be carried into tissue includes liposomes or emulsions ofcollagen, collagen peptides or other components of skin or basementmembrane. Non-limiting examples of neutralization of charge includedelivery of the pharmaceutical agent in the form or an ester or saltwhich is electronically neutral. In some embodiments, the hostilebiophysical environment may include any two or more of these conditions.For instance, the hostile biophysical environment may include high ionicstrength and a high pH or a low pH, a highly hydrophobic environment anda high pH or a low pH, a highly hydrophobic environment that includesliposomes, or the like.

A hostile biophysical environment may also be created in someembodiments by placing a pharmaceutical agent that is relatively highlycharged into a hydrophobic, oily environment such as in an oil-basedcream or lotion containing little or no water. Absorption may further beaided by combining the use of hostile biophysical environments with theuse of penetrating agents, as further described herein.

In one set of embodiments, the composition may be present as anemulsion. As known by those of ordinary skill in the art, an emulsiontypically includes a first phase (e.g., a discontinuous phase) containedwithin a second fluid phase (e.g., a continuous phase). Thepharmaceutical agent (e.g., an H₁ antihistamine) may be present ineither or both phases. In addition, other materials such as thosedescribed herein may be present in the same phase as the pharmaceuticalagent.

In some embodiments, an emulsion may be prepared to contain a drug (orother pharmaceutical agent) of interest in a hostile biophysicalenvironment, and optionally one or more of a stabilization polymer,propylene glycol, and/or a polysorbate surfactant. An emulsion may alsocomprise a nitric oxide donor in some embodiments, for example,L-arginine and/or L-arginine hydrochloride.

In some embodiments, various aspects of the invention relate to methodsand compositions for preparing and/or manufacturing drug formulationsfor topical delivery. In one set of embodiments, the present inventionis generally directed to emulsions that contain one or more drugs orother pharmaceutical agents described herein for topical application. Insome embodiments, certain aspects of the invention are useful forpreparing emulsions that contain one or more drugs (or otherpharmaceutical agents) in a hostile biophysical environment. In someembodiments, the hostile biophysical environment is a high saltconcentration (e.g., a high concentration of one or more salts), forexample, as described herein.

In some embodiments, an emulsion is prepared by mixing a first aqueouspreparation (e.g., a water phase) with a second non-aqueous preparation(e.g., an oil or lipid phase). Drugs or other pharmaceutical agents thatare water-soluble may be added to the first aqueous preparation (e.g.,prior to mixing with the second non-aqueous preparation). Drugs or otherpharmaceutical agents that are water insoluble (or relatively waterinsoluble) may be added to the second non-aqueous preparation (e.g.,prior to mixing with the first aqueous preparation). Drugs or otherpharmaceutical agents that are partially water soluble may be added toone phase, or may be split between the two phases prior to mixing. Thesplit between the two phases will depend on the amount of drug (or otherpharmaceutical agent) that is being added, the composition (e.g., thenature and the amount of other chemicals or agents) of the first andsecond preparations, the pH, the temperature, other physical or chemicalfactors, and/or a combination thereof. For example, if a drug ofinterest is soluble at a 1% level in the aqueous (e.g., water or buffer)phase, but a 2% level of the drug is required in the emulsion, then thedrug may also be added to the non-aqueous (e.g., lipid) phase at a 1%level. In some embodiments, a drug that is less than 1% soluble in anaqueous phase is provided in the non-aqueous phase prior to mixing.However, it should be appreciated that other percentages and/or splitsbetween the two phases may be used.

In some embodiments, the pH of one or both of the first and secondpreparations is adjusted to optimize the solubility of the drug beingused. In some embodiments, a high salt concentration is used. In orderto prevent a high salt concentration from breaking down an emulsion, oneor more emulsifying agents may be used in some cases. In someembodiments, the mixing time may be adjusted to promote appropriatemixing and/or emulsion formation.

In some embodiments, the temperature of the first and/or secondpreparation may be controlled to promote solubility, mixing, and/oremulsion formation. In some embodiments, the temperature of one or bothpreparations and/or of the mixing may be set at 25° C. or higher (e.g.,30° C. or higher, 40° C. or higher, 50° C. or higher, 60° C. or higher,70° C. or higher, or 80° C. or higher). For example, the temperature maybe at between 30° C. and 90° C., between 40° C. and 80° C., at around50° C., at around 60° C., or at around 70° C.

It should be appreciated that methods and compositions of the inventionmay be used with any suitable drug or pharmaceutical agent. In someembodiments, for example, an oral drug may be formulated for topicaldelivery using one or more compositions or methods described herein. Atopical formulation may be useful to deliver a locally effective amountof a drug (or other pharmaceutical agent) to a subject (e.g., a human)without causing unwanted side effects associated with systemic levelsrequired for effectiveness when the drug is administered orally.Accordingly, a topical formulation may be useful to deliver an amount ofa drug that is sufficient to cause a desired effect (e.g., a therapeuticeffect) but that is lower than the total amount of the drug that wouldbe administered to a subject (e.g., a human) if it were provided orally.

Emulsions of the invention may be packaged using any suitable format(e.g., in a tube, a pump-actuated container, or any other suitableform), in certain embodiments of the invention. For example, in someembodiments, an emulsion may be added to a surface of a patch orbandage. The emulsion may also be applied to the skin of a subject as acream, gel, liquid, lotion, spray, aerosol, or the like.

Methods and compositions such as any of those discussed herein may beused to prepare a composition that is sterile or that has a lowmicrobial content, in some embodiments.

In some aspects of the invention, a composition of the invention isadministered to a subject using a delivery vehicle such as a cream, gel,liquid, lotion, spray, aerosol, or transdermal patch. In one set ofembodiments, a composition of the invention may be applied orimpregnated in a bandage or a patch applied to the skin of a subject. Insome embodiments, a patch has a skin contacting portion made of anysuitable material that is covered or impregnated with a cream oremulsion described herein, wherein the skin contacting portion may besupported by a backing, one or both of which may have an adhesivesegment or other configuration for attaching to the skin surface of asubject. A “subject,” as used herein, means a human or non-human animal.Examples of subjects include, but are not limited to, a mammal such as adog, a cat, a horse, a donkey, a rabbit, a cow, a pig, a sheep, a goat,a rat (e.g., Rattus Norvegicus), a mouse (e.g., Mus musculus), a guineapig, a hamster, a primate (e.g., a monkey, a chimpanzee, a baboon, anape, a gorilla, etc.), or the like. Such delivery vehicles may beapplied to the skin of a subject, such as a human subject. Examples ofdelivery vehicles are discussed herein. The delivery vehicle may promotetransfer into the skin of an effective concentration of the nitric oxidedonor and/or the pharmaceutical agent, directly or indirectly. Forinstance, the delivery vehicle may include one or more penetratingagents, as further described herein. Those of ordinary skill in the artwill know of systems and techniques for incorporating a nitric oxidedonor and/or a pharmaceutical agent within delivery vehicles such as acream, gel, liquid, lotion, spray, aerosol, or transdermal patch. Insome cases, the concentration of the nitric oxide donor, and/or apharmaceutical agent in the delivery vehicle can be reduced with theinclusion of a greater amount or concentration of penetrating agent, orincreased to lengthen the beneficial effect. In one set of embodiments,the nitric oxide donor and/or the pharmaceutical agent may be used inconjunction with an adjunct, such as theophylline (for example, at 10%weight by volume).

Other materials may be present within the delivery vehicle, for example,buffers, preservatives, surfactants, etc. For instance, the cream mayinclude one or more of water, mineral oil, glyceryl stereate, squalene,propylene glycol stearate, wheat germ oil, glyceryl stearate, isopropylmyristate, steryl stearate, polysorbate 60, propylene glycol, oleicacid, tocopherol acetate, collagen, sorbitan stearate, vitamin A and D,triethanolamine, methylparaben, aloe vera extract, imidazolidinyl urea,propylparaben, PND, and/or BHA.

As specific non-limiting examples, a cream may have one or more of(w/v): water (20-80%), white oil (3-18%), glyceryl stearate (0.25-12%),squalene (0.25-12%), cetyl alcohol (0.1-11%), propylene glycol stearate(0.1-11%), wheat germ oil (0.1-6%), polysorbate 60 (0.1-5%), propyleneglycol (0.05-5%), collagen (0.05-5%), sorbitan stearate (0.05-5%),vitamin A (0.02-4%), vitamin D (0.02-4%), vitamin E (0.02-4%),triethanolamine (0.01-4%), methylparaben (0.01-4%), aloe vera extract(0.01-4%), imidazolidinyl urea (0.01-4%), propylparaben (0.01-4%), BHA(0.01-4%), L-arginine hydrochloride (0.25-25%), sodium chloride(0.25-25%), magnesium chloride (0.25-25%), and/or choline chloride(0.25-25%). The percentages of each compound can vary (or the compoundmay be absent in some cases), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%,8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.

In another embodiment, the cream may include a pharmaceutical agent, forinstance, an H₁ antihistamine, and one or more of the following, in anysuitable amount: water (e.g., 20-80%), L-arginine hydrochloride (e.g.,0-25%), sodium chloride (e.g., 0-25%), potassium chloride (e.g., 0-25%),glyeryl steareate (e.g., 0-15%), cetyl alcohol (e.g., 0-15%), squalene(e.g., 0-15%), isopropyl mysterate (e.g., 0-15%), oleic acid (e.g.,0-15%), Tween 20 (e.g., 0-10%), and/or butanediol (e.g., 0-10%). Thepercentages of each compound can vary (or the compound may be absent insome cases), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%,12%, 13%, 14%, 15%, 20%, etc.

In some embodiments, the cream may include a pharmaceutical agent, andone or more ionic salts at a concentration at least sufficient toproduce a hostile biophysical environment with respect to thepharmaceutical agent. For example, the cream may include one or more of(w/v): a charged and/or hydrogen bonding entity (0.001-30%), cholinechloride (1-30%), sodium chloride (2-30%), and/or magnesium chloride(1-20% w/v). In another example, the cream may include one or more of(w/v): L-arginine hydrochloride (2.5-25%), choline chloride (10-30%),sodium chloride (5-20%), and/or magnesium chloride (5-20%). In stillanother example, the cream may include one or more of (w/v): creatine(0.001-30%), inosine (0.001-30%), choline chloride (1-30%), sodiumchloride (2-30%), magnesium chloride (1-20%), L-arginine (0.1-25%),and/or theophylline (0.1-20%). In some cases, the cream may also containL-arginine hydrochloride (0-12.5% w/v) and/or theophylline (0-10% w/v).The percentages of each compound can vary (or the compound may be absentin some cases), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,11%, 12%, 13%, 14%, 15%, 20%, etc. In these examples, choline chloride,sodium chloride, and/or magnesium chloride can be used to provide a highionic strength environment.

In some embodiments, the composition may include an antioxidant, whichmay be able to reduce or inhibit the oxidation of other molecules withinthe composition. Examples of suitable antioxidants include, but are notlimited to, glutathione, vitamin C, and vitamin E as well as enzymessuch as catalase, superoxide dismutase and various peroxidases. Theantioxidant may be present in any suitable concentration. For example,the antioxidant may be present at a concentration of at least about0.1%, at least about 0.3%, at least about 0.5%, at least about 0.7%, atleast about 1%, at least about 2%, at least about 3%, at least about 4%,or at least about 5% by weight of the composition. In certainembodiments, the pharmaceutical agent may be present at a concentrationof no more than about 0.2%, no more than about 0.5%, no more than about1%, no more than about 2%, no more than about 3%, no more than about 4%,or no more than about 5% by weight of the composition.

The composition may also be light-sensitive, in certain embodiments.Thus, in some cases, the composition may be contained within a dark oropaque container. In certain embodiments, the composition is alsoprepared under low-light conditions.

Another set of embodiments is generally directed to compositions havingrelatively high temperature stability. For example, the composition maybe stable at elevated temperatures such as at least 40° C. (at leastabout 104° F.) for periods of time of at least about a day. In someembodiments, for instance, a composition of the present invention mayfurther include a stabilization polymer, propylene glycol, and apolysorbate surfactant. Non-limiting examples of stabilization polymersinclude xanthan gum, KELTROL® BT and/or KELTROL® RD; an example of apolysorbate surfactant is Polysorbate 20. Additional examples arediscussed herein.

Such a combination of components to create high temperature stabilityare surprising, since compositions involving any two of these components(but not the third) were found to lack such high temperaturestabilization properties. It is not currently known why this combinationof components is remarkably effective at facilitating relatively hightemperature stability of the compositions discussed herein, as thesecomponents are not known to participate in any significant chemicalreactions with each other, and high temperature stability is greatlyreduced when one of the components is removed. In addition, propyleneglycol is not known to work in pharmaceutical compositions as astabilizing agent.

For instance, in one set of embodiments, a composition may be determinedto be one that has high temperature stability by determining whether thecomposition exhibits phase separation over a relatively long period oftime, e.g., over at least an hour, at least about 2 hours, at least aday, at least about a week, at least about 4 weeks, etc. For example, insome embodiments, a composition is exposed to ambient temperature andpressure for at least 1 hour, and the composition is then analyzed todetermine whether the composition exhibits phase separation or a changein phase. A stable compound is one that exhibits no phase separation,whereas an unstable compound may exhibit phase separation. Suchstability may be useful, for example, for storage of the composition,transport of the composition, shelf life, or the like.

As used herein, a “stabilization polymer” is a polymer that comprisesxanthan gum, a xanthan gum derivative, and/or a xanthan gum equivalent,for example, KELTROL® BT and/or KELTROL® RD, KELZAN® XC, KELZAN® XCD,KELZAN® D, KELZAN® CC, XANTURAL® 180, XANTURAL® 75, or the like, all ofwhich can be obtained commercially from various suppliers. In someembodiments, combinations of these and/or other polymers are alsopossible. In some cases, the stabilization polymer is chosen to be onewhich is at least generally regarded as safe for use in humans. Inaddition, in certain embodiments, the stabilization polymer is producedsynthetically, and/or one which has been purified to some degree. Thestabilization polymer may have any suitable molecular weight, forexample, at least about 1 million, at least about 2 million, at leastabout 5 million, at least about 10 million, at least about 25 million,or at least about 50 million.

The stabilization polymer may be present at any suitable concentrationwithin the composition. For example, the stabilization polymer may bepresent at a concentration of at least about 0.1%, at least about 0.2%,at least about 0.3%, at least about 0.4%, at least about 0.5%, at leastabout 0.6%, at least about 0.7%, at least about 0.8%, at least about0.9%, or at least about 1% by weight of the composition. In someembodiments, the stabilization polymer may be present at a concentrationof no more than about 0.1%, no more than about 0.2%, no more than about0.4%, no more than about 0.6%, no more than about 0.8%, no more thanabout 1%, no more than about 2%, no more than about 3%, no more thanabout 4%, no more than about 5%, no more than about 7%, no more thanabout 10%, no more than about 12%, no more than about 15%, or no morethan about 20% by weight of the composition. In some cases, more thanone stabilization polymer may be present, and each stabilization polymermay be present in any suitable amount. As a specific example, in certainembodiments, the stabilization polymer consists essentially of KELTROL®BT and/or KELTROL® RD. In certain instances, the stabilization polymermay have a fixed ratio of KELTROL® BT and/or KELTROL® RD, for example,1:1 or 3:5 by weight. In another example, the KELTROL® BT may be presentat a concentration of about 0.3% by weight and the KELTROL® RD may bepresent at a concentration of 0.5% by weight of the composition, or oneor both of these may be present at one of the other concentrationsdescribed above. Combinations of these and/or other stabilizationpolymers are also contemplated in other embodiments, e.g., KELTROL® BTand xanthan gum, KELTROL® RD and xanthan gum, etc. In some cases,thickening agents can be used instead of, or in conjunction with astabilization polymer. Many thickening agents can be obtainedcommercially. Thickening agents include those used in the food industry,or are GRAS agents (generally regarded as safe), e.g., alginin, guargum, locust bean gum, collagen, egg white, furcellaran, gelatin, agar,and/or carrageenan, as well as combinations of these and/or otherstabilization polymers. It should thus be appreciated that, in thespecification herein, references to stabilization polymers, in otherembodiments, should be understood to also include thickening agents inconjunction or instead of stabilization polymers,

Propylene glycol can be obtained commercially, and can be present as anystereoisomer or racemic mixture of isomers. It may also be present atany suitable concentration. For instance, propylene glycol may bepresent at a concentration of at least about 1%, at least about 2%, atleast about 3%, at least about 4%, at least about 5%, at least about 6%,at least about 7%, at least about 8%, at least about 9%, or at leastabout 10% by weight of the composition. In some embodiments, propyleneglycol may be present at a concentration of no more than about 2%, nomore than about 4%, no more than about 6%, no more than about 8%, nomore than about 10%, no more than about 12%, no more than about 15%, nomore than about 20%, or no more than about 25% by weight of thecomposition. In some cases, other glycols can be used in conjunction orinstead of propylene glycol, such as butylene glycol. Accordingly, itshould thus be appreciated that, in the specification herein, referencesto propylene glycol, in other embodiments, should be understood to alsoinclude other glycols (e.g., a low molecular weight glycol, or apolyglycol, as described herein) in conjunction or instead of propyleneglycol.

In addition, a polysorbate surfactant can also be present any suitableconcentration within the composition. For instance, in some cases, thepolysorbate surfactant may be present at a concentration of at leastabout 1%, at least about 2%, at least about 3%, at least about 4%, atleast about 5%, at least about 6%, at least about 7%, at least about 8%,at least about 9%, or at least about 10% by weight of the composition.In certain embodiments, the polylsorbate surfactant may be present at aconcentration of no more than about 2%, no more than about 4%, no morethan about 6%, no more than about 8%, no more than about 10%, no morethan about 12%, no more than about 15%, no more than about 20%, or nomore than about 25% by weight of the composition A “polysorbatesurfactant,” as used herein, is a surfactant comprising a polysorbate.For example, the surfactant may comprise sorbitan monolaurate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan monooleate, or anothersorbitan salt. In some cases, the polysorbate surfactant has a molecularformula:

where w, x, y, and z are any suitable positive integers. w, x, y, and zmay also each be independently the same or different. In one set ofembodiments, w+x+y+z is 20 (e.g., as in Polysorbate 20). In some cases,other polymeric sugars can be used instead of, or in conjunction with, apolysorbate surfactant. Thus, it should be appreciated that, in thespecification herein, references to a polysorbate surfactant are by wayof example, and in other embodiments, it should be understood thatreferences to a polysorbate surfactant may include other polymericsugars in conjunction or instead of a polysorbate surfactant.

In some cases, the composition may have a fixed ratio of thestabilization polymer to propylene glycol to the polysorbate surfactant.For instance, the ratio of these may be about 1:1:1, about 1:6:3, about1:6:2, about 1:7:2, about 1:7:3, about 1.5:1:1, about 1.5:6:3, about1.5:6:4, about 1:6:2.5, about 1:6.25:2.5, about 1:6.25:2.5, etc. Asmentioned above, such ratios may be useful, in certain embodiments ofthe invention, in providing temperature stability to the composition.

In certain aspects of the invention, a pharmaceutical agent may becombined with a penetrating agent, i.e., an agent that increasestransport of the pharmaceutical agent into the skin, relative totransport in the absence of the penetrating agent. In some embodiments,the penetrating agent may define and/or be combined with a hostilebiophysical environment. Examples of penetrating agents includeoleoresin capsicum or its constituents, or certain molecules containingheterocyclic rings to which are attached hydrocarbon chains.

Non-limiting examples of penetrating agents include, but are not limitedto, cationic, anionic, or nonionic surfactants (e.g., sodium dodecylsulfate, polyoxamers, etc.); fatty acids and alcohols (e.g., ethanol,oleic acid, lauric acid, liposomes, etc.); anticholinergic agents (e.g.,benzilonium bromide, oxyphenonium bromide); alkanones (e.g., n-heptane);amides (e.g., urea, N,N-dimethyl-m-toluamide); fatty acid esters (e.g.,n-butyrate); organic acids (e.g., citric acid); polyols (e.g., ethyleneglycol, glycerol); sulfoxides (e.g., dimethylsulfoxide); terpenes (e.g.,cyclohexene); ureas; sugars; carbohydrates or other agents. In certainembodiments, the penetrating agent includes a salt, e.g., as describedherein.

Thus, another aspect of the invention provides for the delivery ofpharmaceutical agents (e.g., drugs, biological compounds, etc.) into thebody, and such treatments may be systemic or localized, e.g., directedto a specific location of the body of a subject, such as the head, oneor more specific muscles, an arm, a leg, the genitals, etc., dependingon the specific application.

In one set of embodiments, pharmaceutical agents are introduced to aidin treatment of medical conditions or diseases, and the symptomsassociated thereof. In some embodiments, the invention provides for thetreatment of medical conditions or diseases and/or ailments usingpharmaceutical agents (for example, to treat a subject diagnosed with amedical condition or disease), and in some cases, the invention providesfor the delivery of a minimum amount of pharmaceutical agents to provideeffective levels of medication to an effected area topically whilelimiting side effects. In some cases, the effective dosage of thepharmaceutical agent may be lower than the effective dosage of thepharmaceutical agent when taken orally. Other embodiments of theinvention provide methods for treating pain, for example, pain frommigraine, pain from arthritis, other headaches, joint pain, muscle painand other types of pain. Accordingly, in some embodiments, a compositionmay be topically applied to a specific location of the body, e.g., to asite of pain. Also, in certain cases, a composition as described hereinmay be used in the preparation of a medicament for treatment of pain, orother diseases or conditions as discussed herein.

In another aspect, the present invention is directed to a kit includingone or more of the compositions discussed herein. A “kit,” as usedherein, typically defines a package or an assembly including one or moreof the compositions of the invention, and/or other compositionsassociated with the invention, for example, as described herein. Each ofthe compositions of the kit may be provided in liquid form (e.g., insolution), or in solid form (e.g., a dried powder). In certain cases,some of the compositions may be constitutable or otherwise processable(e.g., to an active form), for example, by the addition of a suitablesolvent or other species, which may or may not be provided with the kit.Examples of other compositions or components associated with theinvention include, but are not limited to, solvents, surfactants,diluents, salts, buffers, emulsifiers, chelating agents, fillers,antioxidants, binding agents, bulking agents, preservatives, dryingagents, antimicrobials, needles, syringes, packaging materials, tubes,bottles, flasks, beakers, dishes, frits, filters, rings, clamps, wraps,patches, containers, and the like, for example, for using,administering, modifying, assembling, storing, packaging, preparing,mixing, diluting, and/or preserving the compositions components for aparticular use, for example, to a sample and/or a subject.

A kit of the invention may, in some cases, include instructions in anyform that are provided in connection with the compositions of theinvention in such a manner that one of ordinary skill in the art wouldrecognize that the instructions are to be associated with thecompositions of the invention. For instance, the instructions mayinclude instructions for the use, modification, mixing, diluting,preserving, administering, assembly, storage, packaging, and/orpreparation of the compositions and/or other compositions associatedwith the kit. In some cases, the instructions may also includeinstructions for the delivery and/or administration of the compositions,for example, for a particular use, e.g., to a sample and/or a subject.The instructions may be provided in any form recognizable by one ofordinary skill in the art as a suitable vehicle for containing suchinstructions, for example, written or published, verbal, audible (e.g.,telephonic), digital, optical, visual (e.g., videotape, DVD, etc.) orelectronic communications (including Internet or web-basedcommunications), provided in any manner.

In some embodiments, the present invention is directed to methods ofpromoting one or more embodiments of the invention as discussed herein,for example, methods of promoting the making or use of compositions suchas those discussed above, methods of promoting kits as discussed above,or the like. As used herein, “promoted” includes all methods of doingbusiness including, but not limited to, methods of selling, advertising,assigning, licensing, contracting, instructing, educating, researching,importing, exporting, negotiating, financing, loaning, trading, vending,reselling, distributing, repairing, replacing, insuring, suing,patenting, or the like that are associated with the systems, devices,apparatuses, articles, methods, compositions, kits, etc. of theinvention as discussed herein. Methods of promotion can be performed byany party including, but not limited to, personal parties, businesses(public or private), partnerships, corporations, trusts, contractual orsub-contractual agencies, educational institutions such as colleges anduniversities, research institutions, hospitals or other clinicalinstitutions, governmental agencies, etc. Promotional activities mayinclude communications of any form (e.g., written, oral, and/orelectronic communications, such as, but not limited to, e-mail,telephonic, Internet, Web-based, etc.) that are clearly associated withthe invention.

In one set of embodiments, the method of promotion may involve one ormore instructions. As used herein, “instructions” can define a componentof instructional utility (e.g., directions, guides, warnings, labels,notes, FAQs or “frequently asked questions,” etc.), and typicallyinvolve written instructions on or associated with the invention and/orwith the packaging of the invention. Instructions can also includeinstructional communications in any form (e.g., oral, electronic,audible, digital, optical, visual, etc.), provided in any manner suchthat a user will clearly recognize that the instructions are to beassociated with the invention, e.g., as discussed herein.

The following documents are incorporated herein by reference:International Patent Application No. PCT/US98/19429, filed Sep. 17,1998, entitled “A Delivery of Arginine to Cause Beneficial Effects,” byE. T. Fossel, published as WO 99/13717 on Mar. 25, 1999; U.S. patentapplication Ser. No. 11/587,323, filed Oct. 19, 2006, entitled“Transdermal Delivery of Beneficial Substances Effected by a HostileBiophysical Environment,” by E. T. Fossel, published as U.S. PatentApplication Publication No. 2008/0280984 on Nov. 13, 2008; and U.S.patent application Ser. No. 11/587,328, filed Oct. 19, 2006, entitled“Beneficial Effects of Increasing Local Blood Flow,” by E. T. Fossel,published as U.S. Patent Application Publication No. 2009/0105336 onApr. 23, 2009.

Also incorporated herein by reference are International PatentApplication No. PCT/US2005/005726, filed Feb. 23, 2005, entitled“Topical Delivery of a Nitric Oxide Donor to Improve Body and SkinAppearance,” by E. Fossel, published as WO 2005/081964 on Sep. 9, 2005;International Patent Application No. PCT/US2005/013228, filed Apr. 19,2005, entitled “Transdermal Delivery of Beneficial Substances Effectedby a Hostile Biophysical Environment,” by E. Fossel, published as WO2005/102282 on Nov. 3, 2005; International Patent Application No.PCT/US2005/013230, filed Apr. 19, 2005, entitled “Beneficial Effects ofIncreasing Local Blood Flow,” by E. Fossel, published as WO 2005/102307on Nov. 3, 2005; U.S. patent application Ser. No. 08/932,227, filed Sep.17, 1997, entitled “Topical Delivery of Arginine of Cause BeneficialEffects,” by E. T. Fossel, published as 2002/0041903 on Apr. 11, 2002;U.S. patent application Ser. No. 10/201,635, filed Jul. 22, 2002,entitled “Topical Delivery of L-Arginine to Cause Beneficial Effects,”by E. T. Fossel, published as 2003/0028169 on Feb. 6, 2003; U.S. patentapplication Ser. No. 10/213,286, filed Aug. 5, 2002, entitled “Topicaland Oral Arginine to Cause Beneficial Effects,” by E. T. Fossel,published as 2003/0018076 on Jan. 23, 2003; U.S. Pat. No. 5,895,658,issued Apr. 20, 1999, entitled “Topical Delivery of L-Arginine to CauseTissue Warming,” by E. T. Fossel; U.S. Pat. No. 5,922,332, issued Jul.13, 1999, entitled “Topical Delivery of Arginine to Overcome Pain,” byE. T. Fossel; U.S. Pat. No. 6,207,713, issued Mar. 27, 2001, entitled“Topical and Oral Delivery of Arginine to Cause Beneficial Effects,” byE. T. Fossel; and U.S. Pat. No. 6,458,841, issued Oct. 1, 2002, entitled“Topical and Oral Delivery of Arginine to Cause Beneficial Effects,” byE. T. Fossel.

In addition, incorporated herein by reference in their entireties areU.S. Provisional Patent Application Ser. No. 61/428,003, filed Dec. 29,2010, entitled “Systems and Methods for Treatment of Allergies and OtherIndications,” by E. T. Fossel; and U.S. Provisional Patent ApplicationSer. No. 61/428,213, filed Dec. 29, 2010, entitled “Methods andCompositions for Preparing Emulsions for Topical Drug Delivery,” by E.T. Fossel.

The following examples are intended to illustrate certain embodiments ofthe present invention, but do not exemplify the full scope of theinvention.

EXAMPLE 1

This prophetic example illustrates one method of preparing a transdermalformula of the invention including fexofenadine, cetirizine,diphenhydramine, or loratadine. The final composition is shown inTable 1. Of course, those of ordinary skill in the art will understandthat percentages other than the ones listed below are also possible,according to other embodiments of the invention.

TABLE 1 Ingredient % w/w Water 35-55 Sodium Chloride 2.5-15  L-ArginineHydrochloride 2.5-15  Fexofenadine, Cetirizine, 0.1-5   Diphenhydramine,or Loratadine Glyceryl Stearate (SE)  4-10 Cetyl Alcohol  4-10 MagnesiumSulfate/Chloride 2.5-15  Squalane 1-8 Xanthan Gum 0.2-2   IsopropylMyristate 0.1-5   Oleic Acid 0.1-5   Propylene Glycol  1-10Polysorbate-20 0.1-5   Vitamin E 0.1-1  

To prepare the formulation in this example, sodium chloride, potassiumchloride, L-arginine and fexofenadine, cetirizine, diphenhydramine, orloratadine were mixed in water, then heated to 74° C. with rapid mixing.In a separate container, the remaining ingredients were mixed togetherand heated to 74° C. The other ingredients were then added to the waterphase at 74° C. with rapid mixing. The mixture was then cooled to roomtemperature with continued mixing. At this point, an emulsion formedwith a relatively thin consistency. The emulsion was then homogenized athigh speed at room temperature to thicken the consistency.

EXAMPLE 2

Initially, it should be appreciated that the compositions described inthis example for the first aqueous and second non-aqueous preparationsfor use with ibuprofen may be used for other drugs or otherpharmaceutical agents such as those described herein (e.g., an H₁antihistamine), or may be modified to contain equivalent or similarcompounds (or a subset thereof) for use with different drugs or otherpharmaceutical agents, and each drug or other pharmaceutical agent mayindividually be provided in the first preparation, the secondpreparation, or both.

Ibuprofen sodium salt is water soluble at pH 7.0 and is added to thewater phase. Any suitable ibuprofen salt may be used. For example, acommercially available ibuprofen salt may be used. In some embodiments,an ibuprofen preparation is manufactured to have the following relativecomposition (Table 2).

TABLE 2 Ingredient Quality % w/w Water USP 40.9 Sodium Chloride USP 10.0L-Arginine Hydrochloride USP 7.5 Ibuprofen USP 7.5 Sodium Hydroxide USP1.3 Glyceryl Stearate (SE) 7.0 Cetyl Alcohol NF 7.0 Potassium ChlorideUSP 5.0 Squalane NF 4.0 Xanthan Gum FCC 0.8 Isopropyl Myristate NF 1.0Oleic Acid NF 1.0 Propylene Glycol USP 5.0 Polysorbate-20 NF 2.0

The basic manufacturing process is to form an emulsion by mixing a waterphase and an oil phase at elevated temperature with rapid mixing. Oncethe two phases are mixed the mixture is cooled to room temperature.While cooling is being accomplished homomixing is accomplished with avertical colloid mill. For example, in one set of embodiments, thefollowing manufacturing steps can be used:

Step 1: disperse xanthan gum in the propylene glycol and water and mixto fully hydrate.

Step 2: To the above mixture add ibuprofen and sodium hydroxide toproduce sodium ibuprofen, add sodium chloride, potassium chloride and1-arginine HCl. Heat this mixture to 75° C. to 80° C.

Step 3: Add glyceryl stearate SE, cetyl alcohol, squalane, isopropylmyristate, oleic acid and polysorbate-20 and heat this mixture to 75° C.to 80° C.

Step 4: Combine the mixtures produced in Step 2 and Step 3 and mix wellmaintaining temperature.

Step 5: Cool the mixture of Step 4 to 25° C. to 30° C. while circulatingthrough the vertical colloid mill.

The resulting smooth emulsion has a pH of 6.50 to 7.50. In some cases,the preparation can be manufactured under conditions to minimizemicrobial content (e.g., completely sterile or with a microbiologicalcontent of less than about 100 CFU/g).

In some embodiments, a transdermal ibuprofen cream is packaged in 100 ml“Magic Star Dispensers” which are airless pumps. The pump dispenses 1.45ml with each depression of the pump head.

In some embodiments, the active compound (e.g., diphenhydramine) may beadded to the aqueous phase prior to mixing with the oil phase. However,other compounds may be added to the oil phase prior to mixing with theaqueous phase.

EXAMPLE 3 Use of a Diphenhydramine Composition

A 19 year old male with a tendency to develop hives was given a creamcontaining 7.5% diphenhydramine in an oil/water emulsion to which 10%sodium chloride and 5% magnesium chloride was added. The pH of the creamwas 7.2. The subject was at an outdoor sporting event when he developeda moderate case of hives over the exposed upper part of his body.Immediately he applied approximately 5 grams of cream and the attackbegan to subside with complete resolution within 20 minutes.

The formula for the topical composition that was used fordiphenhydramine is provided in Table 3 below (shown as % weight). Itshould be appreciated that the relative amounts of each component may bevaried (e.g., by about 10%) in some embodiments. It also should beappreciated that this topical composition may be used for otherantihistamines (e.g., one or more examples of H₁ antihistaminesincluding, but not limited to, fexofenadine, cetirizine (orlevocertrizine), clemastine, diphenhydramine, doxylamine, pheniramine,ebastine, chlorpheniramine, meclizine, embramine, dexchlorpheniramine,and loratadine).

In some embodiments, the active compound may be added to the oil phaseprior to mixing with the aqueous phase. However, other compounds (e.g.,diphenhydramine) may be added to the aqueous phase prior to mixing withthe oil phase.

TABLE 3 Ingredient % purified water 41 propylene glycol 5 xanthum gum0.8 active ingredient 7.5 sodium chloride 10 potassium chloride 0magnesium chloride 5 L-Arginine HCl 7.5 Glyceryl Stearate 6.5 SE CetylAlcohol 6.5 Squalane 3.5 Isopropyl Myrstate 2 Oleic Acid 2 Polysorbate20 2

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

All definitions, as defined and used herein, should be understood tocontrol over dictionary definitions, definitions in documentsincorporated by reference, and/or ordinary meanings of the definedterms.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, unless clearly indicated to thecontrary, in any methods claimed herein that include more than one stepor act, the order of the steps or acts of the method is not necessarilylimited to the order in which the steps or acts of the method arerecited.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

What is claimed is:
 1. A composition for topical delivery to the skin ofa subject, the composition comprising: an ionic salt; a stabilizationpolymer comprising xanthan gum; propylene glycol; a polysorbatesurfactant comprising polysorbate 20; an H₁ antihistamine and/or a saltthereof; and a nitric oxide donor comprising L-arginine and/orL-arginine hydrochloride.
 2. The composition of claim 1, wherein thecomposition is stable when exposed to a temperature of 40° C. for atleast about 4 weeks.
 3. The composition of claim 1, wherein thecomposition is a cream.
 4. The composition of claim 1, wherein thecomposition is contained within a transdermal patch.
 5. The compositionof claim 1, wherein the nitric oxide donor is present at a concentrationof at least about 0.5% by weight of the composition.
 6. The compositionof claim 1, wherein the composition is capable of driving the H₁antihistamine and/or salt thereof through stratum corneum.
 7. Thecomposition of claim 1, wherein the ionic salt is present at aconcentration of at least about 5% by weight of the composition.
 8. Thecomposition of claim 1, wherein the ionic salt comprises one or moresalts selected from the group consisting of sodium chloride, cholinechloride, magnesium chloride, and calcium chloride.
 9. The compositionof claim 1, wherein the composition has an ionic strength of at leastabout 0.25 M.
 10. The composition of claim 1, wherein the compositionhas an ionic strength of at least about 1 M.
 11. The composition ofclaim 1, wherein the composition has a pH of at least about
 7. 12. Thecomposition of claim 1, wherein the composition further comprises apackage containing the nitric oxide donor, the package being selectedfrom the group consisting of liposomes, emulsions of collagen, collagenpeptides and combinations thereof.
 13. The composition of claim 1,wherein the stabilization polymer is present at a concentration of atleast about 0.5% by weight of the composition.
 14. The composition ofclaim 1, wherein the propylene glycol is present at a concentration ofat least about 1% by weight of the composition.
 15. The composition ofclaim 1, wherein the polysorbate surfactant is present at aconcentration of at least about 1% by weight of the composition.
 16. Thecomposition of claim 1, wherein the H₁ antihistamine is fexofenadine.17. The composition of claim 1, wherein the H₁ antihistamine iscetrizine.
 18. The composition of claim 1, wherein the H₁ antihistamineis clemastine.
 19. The composition of claim 1, wherein the H₁antihistamine is diphenhydramine.
 20. The composition of claim 1,wherein the H₁ antihistamine is doxylamine.
 21. The composition of claim1, wherein the H₁ antihistamine is pheniramine.
 22. The composition ofclaim 1, wherein the H₁ antihistamine is ebastine.
 23. The compositionof claim 1, wherein the H₁ antihistamine is chlorpheniramine.
 24. Thecomposition of claim 1, wherein the H₁ antihistamine is meclizine. 25.The composition of claim 1, wherein the H₁ antihistamine is embramine.26. The composition of claim 1, wherein the H₁ antihistamine isdexchlorpheniramine.
 27. The composition of claim 1, wherein the H₁antihistamine is loratadine.
 28. The composition of claim 1, wherein theH₁ antihistamine and/or salt thereof is present at a concentration of atleast about 0.1% by weight of the composition.
 29. The composition ofclaim 1, wherein the composition further comprises an antioxidant. 30.The composition of claim 29, wherein the antioxidant comprises vitaminE.
 31. A method, comprising applying the composition of claim 1 to asubject.
 32. A composition for topical delivery to the skin of asubject, wherein at least about 80% by weight of the compositioncomprises: water; at least one chloride salt; a stabilization polymercomprising xanthan gum; propylene glycol; a polysorbate surfactantcomprising polysorbate 20; an H₁ antihistamine and/or a salt thereof;and a nitric oxide donor.
 33. The composition of claim 32, wherein thecomposition has a pH of at least about
 7. 34. The composition of claim32, wherein the composition further comprises an antioxidant.
 35. Thecomposition of claim 34, wherein the antioxidant comprises vitamin E.36. The composition of claim 34, wherein the antioxidant is present at aconcentration of between about 0.1% and about 1% by weight of thecomposition.
 37. The composition of claim 32, wherein the compositionfurther comprises glyceryl stearate.
 38. The composition of claim 32,wherein the composition further comprises cetyl alcohol.
 39. Thecomposition of claim 32, wherein the composition further comprisessqualane.
 40. The composition of claim 32, wherein the compositionfurther comprises isopropyl myristate.
 41. The composition of claim 32,wherein the composition further comprises oleic acid.
 42. Thecomposition of claim 32, wherein the water is present at a concentrationof at least about 35% by weight of the composition.
 43. The compositionof claim 32, wherein the water is present at a concentration of at leastabout 40% by weight of the composition.
 44. A composition for topicaldelivery to the skin of a subject, the composition consistingessentially of: water; sodium chloride; glyceryl stearate; cetylalcohol; magnesium sulfate and/or magnesium chloride; squalane; astabilization polymer comprising xanthan gum; isopropyl myristate; oleicacid; propylene glycol; a polysorbate surfactant comprising polysorbate20; an antioxidant; an H₁ antihistamine and/or a salt thereof; and anitric oxide donor.
 45. A composition for topical delivery to the skinof a subject, the composition comprising each of the following compoundsat concentrations of no more than ±20% of the stated concentrations:water at a concentration of about 35% to about 55% by weight; sodiumchloride at a concentration of about 2.5% to about 15% by weight;glyceryl stearate at a concentration of about 4% to about 10% by weight;magnesium chloride at a concentration of about 2.5% to about 15% byweight; squalane at a concentration of about 1% to about 8% by weight; apolysorbate surfactant comprising polysorbate 20 at a concentration ofabout 0.2% to about 2% by weight; isopropyl myristate at a concentrationof about 0.1% to about 5% by weight; oleic acid at a concentration ofabout 0.1% to about 5% by weight; propylene glycol at a concentration ofabout 1% to about 10% by weight; a stabilization polymer comprisingxanthan gum at a concentration of about 1% to about 10% by weight; anantioxidant at a concentration of about 0.1 to about 1% by weight; an H₁antihistamine and/or a salt thereof at a concentration of about 0.1% toabout 5% by weight; and a nitric oxide donor at a concentration of about2.5% to about 15% by weight.